title: Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling dyskeratosis congenita.
abstract: The Protection of telomeres 1 (POT1) protein is a single-stranded telomere binding protein that is essential for proper maintenance of telomere length. Disruption of POT1 function leads to chromosome instability and loss of cellular viability. Here, we show that targeted deletion of the mouse Pot1b gene results in increased apoptosis in highly proliferative tissues. In the setting of telomerase haploinsufficiency, loss of Pot1b results in depletion of germ cells and complete bone marrow failure due to increased apoptosis, culminating in premature death. Pot1b(-/-) mTR(+/-) hematopoietic progenitor and stem cells display markedly reduced survival potential in vitro. Accelerated telomere shortening, increased G overhang and elevated number of chromosome end-to-end fusions that initiate an ATR-dependent DNA damage response were also observed. These results indicate an essential role for Pot1b in the maintenance of genome integrity and the long-term viability of proliferative tissues in the setting of telomerase deficiency. Interestingly, these phenotypes closely resemble those found in the human disease dyskeratosis congenita (DC), an inherited syndrome characterized by bone marrow failure, hyperpigmentation, and nail dystrophy. We anticipate that this mouse will serve as a useful model to further understand the pathophysiology of DC.
authors.affiliation: Department of Genetics, The M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Guo
authors.forename: Sonal
authors.initials: S
authors.lastname: Ramchandani
authors.forename: Jin
authors.initials: J
authors.lastname: Ma
authors.forename: Mei-Feng
authors.initials: MF
authors.lastname: Shen
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Garcia
authors.forename: Yibin
authors.initials: Y
authors.lastname: Deng
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.forename: Mingjian James
authors.initials: MJ
authors.lastname: You
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D049109:Cell Proliferation; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency*; D019871:Dyskeratosis Congenita / Q000201:enzymology / Q000235:genetics*; D017353:Gene Deletion; D006238:Haploidy; D006413:Hematopoietic System / Q000002:abnormalities / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009690:Nucleic Acid Conformation; D009928:Organ Specificity; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D019098:Telomerase / Q000172:deficiency* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512707:POT1b protein, mouse; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase